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Background/Objectives: We previously demonstrated that carrying a single pathogenic CFTR allele increases the risk for COVID-19 severity and mortality rate. We now aim to clarify the role of several uncharacterized rare alleles, including complex (cis) alleles, and in trans combinations. Method(s): LASSO logistic regression was used for the association of sets of variants, stratified by MAF, with severity. Immortalized cystic fibrosis bronchial epithelial cell lines and Fischer Rat Thyroid cells were transfected by plasmid carrying specific CFTR mutations. YFP-based assays were used to measure CFTR activity. Result(s): Here we functionally demonstrate that the rare (MAF=0.007) complex G576V/R668C allelemitigates the disease by a gain of function mechanism. Several novel CFTR ultra-rare (MAF <0.001) alleles were proved to have a reduced function;they are associated with disease severity either alone (single or complex alleles) or with another hypomorphic allele in the second chromosome, with a global reduction of CFTR activity between 40 to 72%. Conclusion(s): CFTR is a bidirectional modulator of COVID-19 outcome. At-risk subjects do not have open cystic fibrosis before viral infection and therefore are not easily recognisable in the general population unless a genetic analysis is performed. As the CFTR activity is partially retained, CFTR potentiator drugs could be an option as add-on therapy for at-risk patients.
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B PM1-030 b B Adverse drug reaction profile of drug interactions involving a protein kinase inhibitor indicated in chronic myeloid leukemia from pharmacovigilance databases b M. C. Pajiep, M. Lapeyre-Mestre and F. Despas I Centre Hospitalier Universitaire (CHU) de Toulouse, France i B Introduction: b The introduction of protein kinase inhibitors (PKIs) for chronic myeloid leukemia (CML) has considerably improved prognosis of the disease but has also demonstrated a great potential for drug-drug interactions. Service de Médecine Interne et Infectiologie, Groupe Hospitalier Diaconesses-Croix Saint-Simon, Paris, France i B Introduction: b Despite an important drug-drug interaction, it was previously suggested the clindamycin-rifampicin combination could be used in patients with bone and joints infections (BJIs) provided clindamycin is administered by continuous infusion. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction. Twenty patients received clindamycin without rifampicin, 19 patients received clindamycin concomitantly with rifampicin and the remaining 85 received clindamycin successively without and with rifampicin. B Results: b Among 957 patients treated with anti-PD-1/PD-L1 during the data collection period, 686 patients were included: 430 new users of a SD regimen, 161 patients who started with SD and switched to ED regimen during follow-up, and 95 new users of an ED regimen. [Extracted from the article] Copyright of Fundamental & Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)
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Background: The advent of highly effective modulator therapies (HEMTs), including elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), for treatment of cystic fibrosis (CF) has resulted in remarkable clinical improvement for modulator-naive patients and for those who have been treated with prior modulator therapies. Intranasal micro-optical coherence tomography (muOCT) has detected functional abnormalities in the mucociliary apparatus of people with CF. The objectivewas to characterize the effects of ELX/TEZ/ IVA on nasal mucociliary clearance by muOCT and monitor the clinical changes conferred as a way to understand the effects. Method(s): Of 26 individuals aged 12 and older with at least one F508del mutation recruited, 24 were enrolled and followed over three visits: baseline and 1 (visit 2) and 6 months (visit 4) after initiation of ELX/TEZ/IVA therapy;the COVID-19 pandemic affected visit windows. Intranasal muOCT imaging was conducted at baseline and visit 2 as previously described;additional imaging for 18 months (visit 5) is in progress. Clinical outcomes, including percentage predicted forced expiratory volume in 1 second (FEV1pp) and sweat chloride levels were computed as part of the parent Prospective Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function (PROMISE study). A blinded investigator team analyzed in vivo muOCT parameters including mucociliary transport (MCT) rate, ciliary beat frequency (CBF), and periciliary liquid depth (PCL) after devising an improved stabilization algorithm. Analysis of airway surface liquid (ASL) depthswas excluded because of the limited number of cases in which the necessary condition for measurement,which is preservation of a clear air layer between the mucus layer and the probe, was satisfied. Result(s): Twenty-three subjects completed visits 1 and 2, and 18 completed visits 1, 2, and 4. Average age at baselinewas 27 +/- 8.7, 69% were female, and 43% were on prior two-drug modulator therapy. No significant change in body mass index was found between the visits. FEV1pp increased significantly (10.9%, 95% CI, 76.1-98.4%) by visit 2 and persisted at visit 4 (10.6%, 95% CI, 87.7-107.0;p < 0.001). Sweat chloride levels decreased significantly at visit 2 (-36.6 mmol/L, 95% CI, 40.9-54.9 mmol/L) and visit 4 (-41.3 mmol/L, 95% CI, 34.9-51.8 mmol/L) at visit 4 ( p < 0.001). Analysis of muOCT images revealed significant improvement in MCT rate (2.8 +/- 1.5 mm/ min at baseline vs 4.0 +/- 1.5 mm/min at visit 2, p = 0.048), although no discernable changes were noted in CBF or PCL. When stratified based on use of prior modulator therapy, no significant differences were found for any muOCT metric. No significant correlations between change in MCT rates and change in FEV1pp or sweat chloride from baseline to visit 2were found. Conclusion(s): Treatment with ELX/TEZ/IVA in people with CF, including those that were treatment naive and those on prior modulator therapy, resulted in significant, sustained improvement in lung function and decreases in sweat chloride levels at ~10 months, consistent with recently published reports. Functional improvements in MCTratewere evident after initiation of ELX/TEZ/IVA therapy, which may partially explain the findings of better whole-lung mucus clearance and reduction in chronic infections reported previously. muOCT imaging in people with CF is sensitive to the treatment effect of HEMT and suggests better mucociliary transport as a mechanism of action underlying the clinical benefits for lung health. Acknowledgements: On behalf of the PROMISE investigatorsCopyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: Increasing availability of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) has improved the quality of life and long-term prognosis for many people with CF. Thus, more people with CF are considering parenthood. Almost all menwith CF (MwCF) are infertile because of congenital bilateral absence of the vas deferens (CBAVD). Based on CF animal models, CBAVD occurs early in gestation and is unlikely to be reversible using HEMT, but assisted reproductive techniques (ARTs) can enable MwCF to father children using the sperm in their testes. Animal reproductive models suggest no HEMT teratogenicity, and the amount of exposure of the fetus to HEMT via absorption of seminal fluid through the vaginal wall is predicted to be negligible, although to ensure no sperm exposure to HEMT, the life span of sperm would require MwCF to discontinue CFTR modulators for approximately 3 months before ART. Because abrupt discontinuation of CFTR modulators may result in health decline, MwCF and their providers must consider all potential risks. There are no published data in MwCF regarding use of HEMT during conception and partner pregnancy. Method(s): Beginning in August 2021, CF center staff in the United States, United Kingdom, and Australia completed a two-page anonymous questionnaire regarding MwCF who used CFTR modulators during ART (sperm retrieval and in vitro fertilization) or natural conception with subsequent partner pregnancy. Result(s): Providers have submitted 34 surveys for MwCF on CFTR modulators whose partner became pregnant after use of ART (n = 32) or natural conception (n = 2). The median age of the samplewas 32 (range 24- 43). Fifteen were homozygous for F508del, median percentage predicted forced expiratory volume in 1 second was 76% (range (22-111%), and median body mass index was 24 kg/m2 (range 18.5-32.1). Twenty-three were taking elexacaftor/tezacaftor/ivacaftor. The median time that MwCF were taking CFTR modulators before partner conception was 18 months (range 0-82). One newly diagnosed man initiated HEMT after sperm retrieval. Four MwCF stopped CFTR modulators before sperm retrieval, one of whom experienced pulmonary decline. None of the 19 MwCF whose condom use during pregnancy was known used condoms. Fetal complications in partners of MwCF included three first-trimester miscarriages, two* COVID, two breech presentation, two* vaginal bleeding, and one vasa previa. None of the complications were deemed definitively related to use of CFTR modulators. One MwCF experienced testicular infection after sperm retrieval#. Postpartum complications included three# infants with hypoxemia requiring neonatal intensive care unit stay, three maternal blood loss, one forceps delivery, and one caesarean section. No congenital anomalies were reported for any infant. (*/# overlap). Conclusion(s): Use of CFTR modulator therapy during partner conception and pregnancy in 34 MwCF has not resulted in higher-than-expected miscarriage rates or congenital anomalies. Providers should consider the risk to the health of MwCF combined with the lack of teratogenicity in animal reproductive models and limited safety data in the human fetus before discontinuing CFTR modulators before ART or natural partner conception. Survey collection is ongoing;results will be updated for presentationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: The Cystic Fibrosis Legal Information Hotline (CFLIH) provides information on legal issues affecting people with cystic fibrosis (CF). Since 1998, it has provided the CF community with confidential information on health insurance, Social Security, employment, and education. Method(s): The CFLIH tracks each call according to the age of the person with CF, the caller's relationship to the person with CF, and the subject matter of the call. Result(s): The CFLIH received 10 870 calls in 2021;63% were related to a person with CF aged 18 and older and 37% to a child younger than 18;55% were from a person with CF, 7% more than in 2020;and 22% of calls came from CF centers. Of the 2444 calls from CF centers, 95% were from nonphysician staff and 5% from physicians. Twenty-two percent were from a parent of a person with CF, and 1% of callers were the spouse or someone with another relationship to the person with CF. Fifty-seven percent of calls were related to Social Security benefits, 9% more than in 2020. These calls were evenly divided between Supplemental Security Income and Social Security Disability Insurance. Sixteen percent of calls were related to benefits and coverage under a private or public health benefit plan: 34% of these related to private health benefit plans and 66% related to public health benefit plans. Of the public benefit plans, 53% related to Medicare and 47% to Medicaid. Nine percent of calls were related to CF in primary, secondary, and higher education, 22% more than in 2020, and 18% were related to employment. Conclusion(s): Total calls in 2021 stabilized after a record high of 13 405 in 2020. The surge in calls that began in 2020 was driven by problems caused by the COVID-19 pandemic and continued into 2021. Calls in 2021 exceeded pre-pandemic levels. In 2021, calls related to Social Security were 9% higher than in 2020. The increase in Social Security calls is attributed to persons with CF becoming unable to work because of the progression of CF symptoms, many of whom are not eligible for CF transmembrane conductance regulator (CFTR) modulator therapy. Calls also increased from those whose health had improved with CFTR modulator therapy who sought information about maintaining Social Security or health insurance while returning to work. The increase in Social Security calls is also attributed to an increase in the number of Social Security beneficiaries undergoing reviews of their disability status by the Social Security Administration. Employment calls continued to be higher than pre-pandemic levels. Remote work during the pandemic tended to help workers with CF maintain employment. Return to in-person work raised concerns about workplace safety, reasonable accommodations, and other workplace issues. Loss of employment with reasonable accommodations for CF was a common experience. The CFLIH increased health equity by helping maintain health coverage for vulnerable members of the CF community, which avoids disruptions in coverage and care. During the global COVID-19 pandemic, the CFLIH continues to be a reliable source of information in obtaining Social Security benefits, health insurance, employment, and safe access to educationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), a triple CFTR modulator combination, has proved to be highly effective in Phe508del homozygous and Phe508del/minimal function compound heterozygous people with cystic fibrosis (PwCF).We report preliminary data on the realworld effectiveness and safety of ELX/TEZ/IVA after 6 months of treatment. Method(s):We collected prospective data on PwCF who started ELX/TEZ/IVA and evaluated changes in pulmonary function (spirometry and lung clearance index [LCI]), nutritional status (body mass index [BMI]), sweat chloride, and rate of hospitalization from baseline to 6 months of treatment. Result(s): Between August 2021 and October 2021, ELX/TEZ/IVAwas started in 24 PwCF (12 female,10 Phe508del-homozygous, median age 20.5 (range 13-37), all with pancreatic insufficiency). After 6 months of treatment, all respiratory function indicators improved (median change: +16% percentage predicted forced expiratory volume in 1 second, +12% percentage predicted forced vital capacity, +23% percentage predicted forced expiratory flow at 25/75%, -2 lung clearance index). Improvement was also observed in BMI (+0.41 z-score) and sweat chloride concentrations (-54 mMol/L, 6 PwCF had Cl concentrations within the limit of normality) (Table 1). Over a 6-month period, only one hospitalization due to pulmonary exacerbations was observed, compared with 22 hospitalizations observed in the 6 months before starting ELX/TEZ/IVA (rate per 100 patient-months 15.3 vs 0.7, rate ratio 0.05, 95% CI, 0.01-0.29). Treatment was well tolerated, with only mild and transient adverse events consisting of headache (n = 4), cutaneous rash (n = 2), and mild hemoptysis (n = 2). One PwCF had intestinal subocclusion and required hospitalization. One patient had liver function test elevation after 6 months of therapy during an Changes in clinical variables and sweat test results from baseline through 6 months in patients treated with elexacaftor, tezacaftor and ivacaftor. Data are medians (interquartile ranges). Baseline vs 6 months compared usingWilcoxon signed-rank test. ppFEV1, percentage predicted forced expiratory volume in 1 second;ppFVC, percentage predicted forced vital capacity;ppFEV25/75, percentage predicted forced expiratory flow at 25/75%;LCI, lung clearance index;BMI, body mass index;Cl, chloride. (Table Presented) episode of SARS-COV2 infection, which required adjustment of the dose administered. Conclusion(s): Our data confirm that ELX/TEZ/IVA treatment is safe, well tolerated, and effective in PwCF. ELX/TEZ/IVA improved pulmonary function and nutritional status and remarkably reduced hospitalization rate. Our data indicate that introduction of ELX/TEZ/IVA in CF care will radically change the natural history of and management approach to the disease.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: Dyslipidemias and essential fatty acid deficiencies (EFADs) are well established complications of cystic fibrosis (CF). In the general population, a diet high in saturated fat is associated with hyperlipidemia and greater risk of cardiovascular disease and type 2 diabetes. Increasing life expectancy in CF brings concern about the risks of the "legacy" high-fat CF diet. The impact of CFTR modulators on CF-related dyslipidemia and EFAD is not known. Previous studies reported dyslipidemia in people with CF (PwCF) using traditional lipid measures. This study aimed to evaluate the lipoprotein and fatty acid profiles in children and adolescents with CF and to correlate biochemical results with clinical and molecular findings. Plasma and red blood cell (RBC) samples were studied to compare the ability of each method to identify EFAD markers. Method(s): Blood samples (n = 171) were obtained from 142 (78 female) children with CF aged 9.8 +/- 4.7 (range 4 months to 18 years) during routine laboratory draws at pediatric CF center clinic visits. Pancreatic insufficiency was present in 92% and glucose intolerance or diabetes in 14%. Body mass index percentile (BMI%ile) for age z-scorewas 0.23 +/- 0.89 (range -2.4-2.6). F508del mutation was homozygous for 56% and heterozygous for 41%. CFTR modulator therapy had been initiated 3 or more months before for 62% of samples. Sample collection began in September 2019, paused during the COVID-19 pandemic, and resumed in July 2021. An accredited, regional laboratory with expertise in fatty acid analysis processed all samples. Serum was separated and refrigerated for lipoprotein analysis, plasmawas separated and frozen, and RBCs were washed and frozen for fatty acid analysis. Nuclear magnetic resonance lipoprotein assayswere conducted to determine particle number and size of lipoprotein classes. Triglyceride, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were measured directly (Roche). Low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C) were calculated. To correlate laboratory results with clinical findings, medical records were reviewed, and a CF clinic dietitian conducted 24-hour dietary recalls concurrent with study labs. Result(s): Of PwCF homozygous F508del/F508del, 43% tested positive for EFAD biomarkers (RBC linoleic acid, RBC mead acid, RBC triene/tetraene ratio), compared with 13% of PwCF heterozygous F508del ( p <=0.01) (Figure 1). There was no significant difference in concentrations of fatty acid and EFAD biomarkers between those who had or had not initiated CFTR modulator therapy. Lipoprotein abnormalities were identified in 69% of samples with low HDL-C and 39% with large HDL-C, 87% with large VLDL-C particle size and 52% with large VLDL-C particle number, and 5% with high LDL-C or small LDL-C particle numbers. High total cholesterol was found in 15% and high triglycerides in 17%. HDL-C was low in 24%, and 3% had high LDL-C. (Figure Presented) Figure 1. Differences in concentrations of red blood cell (RBC) linoleic and mead acids and triene/tetraene (T/T) ratio between F508del homozygous and F508del heterozygous individuals Conclusion(s): Despite clinical advances and use of CFTR modulator therapy, EFAD remains prevalent and underrecognized in the pediatric CF population. Of PwCF, those homozygous for f508del may have a higher risk of EFAD. Limitations of this study (four different CFTR modulator therapies and small sample sizes in each group) may have precluded significant findings for EFAD and lipid profiles, but PwCF receiving modulator therapy appear to have healthier lipid profiles than those not receiving therapy. Lipids and fatty acid are not routinely evaluated in PwCF, but evaluation should be included in the standard of care for timely dietary interventionsCopyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: As cystic fibrosis (CF) lung disease progresses, the airways become colonized with opportunistic pathogens such as Pseudomonas aeruginosa secondary to airway surface liquid depletion. Acquisition of P. aeruginosa is associated with decline in lung function and increase in treatment burden and mortality. In October 2019, the Food and Drug Administration approved elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), a highly effective modulator therapy (HEMT) for individuals aged 12 and older with one copy of the F508del CFTR mutation. ELX/TEZ/IVA increases the amount of and function of CF transmembrane conductance regulator (CFTR) in the respiratory epithelium, increasing mucociliary clearance (MCC) and reducing static airway mucous, a major trigger for chronic infection and inflammation. Method(s): A retrospective analysis of inhaled tobramycin (iTOB) prescriptions prescribed between January 1, 2016, and December 31, 2021, was performed. This captured data before and after ELX/TEZ/IVA approval at Children's Mercy Kansas City (CMKC). The number of individuals with new P. aeruginosa acquisition was determined by identifying electronic prescriptions for iTOB eradication courses. An eradication course was defined as a first lifetime prescription for iTOB or a new prescription for iTOB submitted at least 1 year after a previous prescription. The number of individuals considered chronically infected with P. aeruginosa was determined by identifying individuals receiving chronic iTOB prescriptions and confirmed by respiratory cultures indicating chronic infection based on the Leeds criteria (P. aeruginosa recovered in >=50% of airway cultures in the previous 12 months). Result(s): Eradication courseswere prescribed to 34 individuals in 2016 (15% of people receiving care at CMKC). The number of eradication prescriptions declined in 2020 and 2021, with only 15 (7%) individuals prescribed eradication therapy in 2020 and 12 (5%) in 2021. A similar pattern was observed for prescriptions for chronic infection. In 2016, 57 individuals (25% of our patient population) were receiving iTOB for chronic P. aeruginosa infection. Reductions were seen in 2020 and 2021, with 28 (13%) and 20 (9%) individuals prescribed chronic therapy, respectively. The number of individuals prescribed iTOB for P. aeruginosa eradication and chronic infection per year is represented in Figure 1.(Figure Presented)Conclusions: CMKC experienced a decrease in the number of courses of iTOB prescribed over the last 6 years. HEMT use is associated with greater MCC and anti-inflammatory effects affecting the airway microbiome. The decrease in respiratory cultures growing P. aeruginosa likely reflects these phenomena. A confounding factor is the SARS-CoV-2 pandemic and widespread use of HEMT. Clinic closures and implementation of telemedicine limited in-person patient visits during 2020 and 2021. Despite limited in-person visits, the average number of respiratory cultures per individual at CMKC in 2020 was 3.5, which is consistent with previous years.Wewere able to obtain frequent surveillance cultures through implementation of a drive-through respiratory specimen collection process. Hence, the decrease in number of iTOB courses cannot be attributed to a decrease in frequency of respiratory cultures, although we cannot assess the impact of school closures and a decrease in social gatherings on new P. aeruginosa acquisition or chronic infection. Looking at all these variables, the widespread use of HEMT likely played a significant role in reducing new P. aeruginosa acquisition and chronic P. aeruginosa infection.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: Polymorphonuclear neutrophils (PMNs) recruited to the airway lumen in cystic fibrosis (CF) undergo a rapid transcriptional program, resulting in exocytosis of granules and inhibition of bacterial killing. As a result, chronic infection, feed-forward inflammation, and structural tissue damage occur. Because CF airway PMNs are also highly pinocytic, we hypothesized that we could deliver protein- and ribonucleic acid (RNA)-based therapies to modulate their function to benefit patients. We elected to use extracellular vesicles (EVs) as a delivery vector because they are highly customizable, and airway PMNs have previously been shown by our group to process and use their cargo efficiently [1]. Furthermore, our prior work on CF airway PMNs [2] led to identification of the long noncoding RNA MALAT1, the transcription factor Ehf, and the histone deacetylase/long-chain fatty deacylase HDAC11 as potential targets to modulate CF airway PMN dysfunction. Method(s): H441 human club epithelial cells were chosen for EV production because they efficiently communicate with lung-recruited primary human PMNs [1]. Relevant constructs were cloned into an expression plasmid downstream of a constitutive cytomegalovirus or U6 promoter with an additional puromycin selection cassette. EVs were generated in serumdepleted media and purified by differential centrifugation. Quality and concentration of EVs was determined by electron microscopy and nanoparticle tracking analysis and cargo content by western blot (protein) or qualitative reverse transcription polymerase chain reaction (RNA). Enhanced green fluorescent protein and messenger ribonucleic acid (mRNA) were used as controls. To test delivery to primary human PMNs, generated EVs were applied in the apical fluid of an airway transmigration model [2]. PMN activation was assessed by flow cytometry, and bacterial (PA01 and Staphylococcus aureus 8325-4) killing and viral (influenza Avirus [IAV] H1N1/PR/8/34;SARS-CoV-2/Washington) clearance assays were conducted. Result(s): To package protein, we used EV-loading motifs such as the tetraspanin CD63, Basp1 amino acids 1-9, and the palmitoylation signal of Lyn kinase. To load mRNA, a C'D box motif recognized by the RNA-binding protein L7Ae was included in the 3' untranslated region of the expressed RNA, and CD63-L7Ae was co-expressed. Airway-recruited PMNs treated with EVs containing small interfering RNAs against MALAT1 or HDAC11 showed greater ability to clear bacteria. Conversely, PMNs treated with constructs encasing MALAT1 or HDAC11 efficiently cleared IAV and SARSCoV- 2. PMNs expressing Ehf showed greater clearance of bacteria and viruses. Conclusion(s): Our findings suggest mutually exclusive roles of MALAT-1 and HDAC11 in regulating bacterial and viral clearance by airway-recruited PMNs. Expression of Ehf in airway PMNs may be a pathogen-agnostic approach to enhancing clearance by airway-recruited PMNs. Overall, our study brings proof-of-concept data for therapeutic RNA/protein transfer to airway-recruited PMNs in CF and other lung diseases and for use of EVs as a promising method for cargo delivery to these cells. It is our expectation that, by treating the immune compartment of CF airway disease, pathogentherapies, such as antibiotics will be more effective, and epithelial-targeted therapies, such as CFTR modulators, will have greater penetrance into the cell types of interest.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: Air-liquid interface (ALI) and organoid culture are key techniques for differentiating human airway epithelial cells (HAECs). The efficiency and robustness of these assays often depends on the quality of primary-isolated cells, but primary cell isolation workflows, with which the user controls the choice of isolation method, cell culture medium, and culture format, may reduce reproducibility. Therefore, an optimized, standardized workflow can enhance and support isolation of epithelial cells from diseased donors with potentially rare cystic fibrosis (CF) mutations or particularly sensitive cell populations. We have developed a standardized workflow for isolation and culture of freshly derived airway epithelial cells. Method(s): Briefly, HAECs isolated from primary tissue were expanded in PneumaCult-Ex Plus Medium for 1 week and then seeded into Corning Transwell inserts and expanded until confluency. The cells were then differentiated in PneumaCult-ALI Medium for at least 4 weeks. To assess differentiation efficiency in ALI culture, the cells were immunostained to detect Muc5AC, acetylated tubulin, and ZO-1 to identify goblet cells, ciliated cells, and apical tight junctions, respectively, aswell as SARS-CoV-2 cell entry targets angiotensin-converting enzyme 2 and transmembrane serine protease 2. Ion transport and barrier function of the ALI culturesand response to CF transmembrane conductance regulator (CFTR) correctors were also measured. In addition, freshly derived HAECs were seeded into Corning Matrigel domes in the presence of PneumaCult Airway Organoid Seeding Medium. Oneweek later, the mediumwas changed to PneumaCult Airway Organoid Differentiation Medium and maintained for an additional 3 weeks to promote cell differentiation. These airway organoids were then treated with CFTR corrector VX-809 for 24 hours, followed by 6-hour treatment with amiloride, forskolin, and genistein to induce organoid swelling. Result(s): Our results demonstrate that ALI cultures derived from CF donors displayed partial rescue of CFTR across multiple passages after treatment with VX-809. Airway organoids were found to express functional CFTR, as evidenced by forskolin treatment, which induced a 64 +/- 14% (n = 1 donor) greater organoid area than in vehicle control-treated airway organoids. Airway organoids derived from CF donors displayed a loss of forskolininduced swelling, which could be partially re-established with VX-809 treatment (29 +/- 9%, n = 3). Conclusion(s): In summary, the PneumaCult workflow supports robust, efficient culture of primary-airway epithelial cells that can be used as physiologically relevant models suitable for CF research, CFTR corrector screening, and studying airway biology.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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AimRespiratory failure remains the most common cause of death in Cystic Fibrosis (CF) with chronic/complex infection a significant contributory factor. Infection frequency and associated treatment burden increase the risk drug-resistant organisms;however, stewardship strategies are challenging to translate to CF care.The CFTR modulator Kaftrio® (elexacaftor/tezacaftor/ivacaftor) launched in the UK in August 2020. Initial phase 3 clinical trials1 2 and a subsequent open-label extension study3 demonstrated promising data on health-related quality of life, including reduced pulmonary exacerbation (PEx) rates (63%), hospitalisation (71%) and PEx requiring IV antibiotics (78%). This evaluation aimed to provide a ‘real-world' review of the impact of Kaftrio® on IV antibiotic burden (admission rates, ‘bed-days', bed-day cost, total IV antibiotic use and ‘AWaRE' antibiotic use) in CF patients aged 12–16 years at a single tertiary centre.MethodA single-centre retrospective observational evaluation was conducted. All 12–16 year olds on Kaftrio® were identified using the local CF database. For each patient: month/year Kaftrio® commenced and prior CFTR modulator therapy were determined. Clinical trial patients were excluded. Digital clinical information systems were used to identify ‘chest-related' admissions for IV antibiotics in the 24 months prior to starting Kaftrio® and the treatment period post, up to June 2022. For each admission, drugs, doses administered and ‘IV antibiotic bed-days' were determined. ‘Bed-day' costs were calculated and use of ‘Restricted' or ‘Watch' antibiotics (WHO AWaRE/local Policy) were identified. IV antibiotic burden pre- and post Kaftrio® was evaluated.Results44 admissions in 33 patients were identified prior to Kaftrio®, compared with 13 admissions post-Kaftrio®, demonstrating a 65–70% overall reduction in admissions (PEx: rate 66/100patient/year vs 23/100patient/year). Pre-Kaftrio® 639 ‘bed days'/24 months were directly attributed to delivery of IV antibiotics-a total estimated cost of £383,400 (estimate £600/day/medical bed). From October 2020-June 2022, the number of IV antibiotic ‘bed days' fell to 183. A total reduction of 71%, with an estimated cost saving of £273,600. In the 24 months prior to Kaftrio® a total 2849 doses of IV antibiotics were administered vs 657 doses in the same patient cohort in the period post-Kaftrio® to June 2022, an absolute reduction of 2192 doses (77%). Of the 2849 IV antibiotics pre-Kaftrio® doses, 84% were restricted/watch antibiotics (R=706;W= 1681). Usage dropped by 37.5% and 89% respectively post-Kaftrio®.ConclusionResults suggest Kaftrio® reduces overall IV antibiotic burden in CF patients, providing real-word data supporting the phase 3 study outcomes. Significant reductions in PEx rates, IV antibiotic use, ‘bed days' and associated costs were all observed. Data demonstrated an absolute reduction in the use of ‘AWaRE' antibiotics, although use still accounts for a high overall proportion in this cohort. Results are limited by the data periods. Potential impact of the COVID-19 pandemic on PEx rates (‘shielding' population) should be considered. Nonetheless, the significance of these findings on overall outcomes and stewardship should not be downplayed. Ongoing review, including expanded patient populations (adults;6–11 years) is essential. Further works looking at oral antibiotics use, epidemiology, genotype and previous CFTR treatment would support extended evaluation of the overall impact of Kaftrio® on infection management in CF.ReferencesMiddleton PG, Mall MA, Drevineck P, et al. Elexacaftor-tezacaftor-ivacaftor for Cystic Fibrosis with a single Phe508del Allele. New England Journal of Medicine 2019;381:1809–1819.Southern K, Murphy J, Sinha I, et al. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants. Cochrane Database of Systematic Review 2020;12;1–313.Griese M, Costa, S, Linnemann R, et al. Safety and e ficacy of Elexacaftor/Tezacaftor/Ivacaftor for 24 weeks or longer in people with cystic fibrosis and one or more F598del Allele: Interim Results of an Open-Label Phase 3 Clinical Trial. American Journal of Respiratory and Critical Medicine 2021;203;381–384.
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Background and AimFor most of the 83 years since acknowledging cystic fibrosis (CF) as a separate disease entity, treatment has primarily focused on symptomatic relief.1 Following the discovery of the CFTR gene, efforts have been made to produce therapies to target the underlying dysfunctions caused by CFTR mutations.2 Moderate transaminase elevations are commonly observed in CF patients. Severe transaminase elevations have been observed in patients taking CFTR modulators in clinical trials with the initial STRIVE trial revealing that treatment discontinuation was commonly due to an increase in hepatic enzymes.3 Consequently, liver function test (LFTs) monitoring is recommended for all patients before commencing therapy, every three months for the first year and annually thereafter. This audit aims to assess the compliance of LFT monitoring in clinical practice for paediatric patients initiated on CFTR modulators, evaluate the incidence of liver-related adverse effects, and examine trends between the CFTR modulator used and the clinical significance of LFT derangements, and determine if there are any sex-related correlations.MethodsPatient data, including date and age on treatment initiation, gender, LFT results at baseline (AST, ALT, ALP, GGT and total bilirubin), first derangement since initiation and monitoring frequency were extracted from the clinical system Meditech®, pseudonymised and analysed. There were 91 records of patients being treated with a CFTR modulator. Some patients were on more than one CFTR modulator as treatment can be switched if eligible. For the purpose of the audit after consultation with the local CF clinical team, a two-month deviation outside of the recommended monitoring frequency was considered non-compliant. LFT derangements were classified as clinically significant if the result was higher than 3 times the upper limit of normal (ULN).ResultsOur study found that most patients (50/91 – 54.9%) on CFTR modulators in the tertiary centre did not have their LFTs monitored following the recommended guidelines. A statistically significant increase in LFT abnormalities from pre- to post- intervention with a CFTR modulator was observed (p=0.015). Kaftrio®/Kalydeco® (3/20 – 15%) and Orkambi® (1/29 – 3.4%) were the only CFTR modulators that led to patients developing clinically significant derangements (>3x ULN). Additionally, a greater proportion of females (24/51 – 47.1%) than males (15/40 – 37.5%) had abnormal LFTs within the tertiary centre contrary to previous epidemiological studies where males have been documented to have a greater risk of abnormal LFTs. However, the strength of this association was negligible (φ =0.096, p=0.360).ConclusionIn conclusion, the tertiary centre's compliance with LFT monitoring guidelines for patients initiated on CFTR modulators was substandard. Most records of treatment initiation occurred during COVID-19, which impacted monitoring as many hospitals suspended routine clinical work to limit the spread of the infection in high-risk groups. Time constraints limited the audit during the data extraction period;therefore, results should be interpreted cautiously. In the absence of the COVID-19 pandemic a re-audit process should include patient lifestyle data and consider other medication regimens that could potentially alter LFTs. Introducing a blood clerk would enable the CF unit to monitor LFT changes more efficiently.ReferencesGuimbellot J, Taylor-Cousar JL. Combination CFTR modulator therapy in children and adults with cystic fibrosis. The Lancet Respiratory Medicine 2021;9:677–679.Lopes-Pacheco M. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine. Frontiers of Pharmacology 2020;10:1662.Gavioli EM, Guardado N, Haniff F, et al. A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators. Journal of Clinical Pharmacy and Therapeutics 2021;46:286–294.
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Objective: Following the creation of a quality improvement (QI) lead in the Oxford adult CF service, key areas for development were identified. Increased use of virtual care and CFTR modulators highlighted a need to adapt our transition process to meet the changing needs of young people with CF (pwCF). Our aim was to facilitate collaboration across adult and paediatric teams to identify areas for improvement. Method: We led a process of stakeholder engagement including meeting with other CF and non-CF transition services. Multidisciplinary Team (MDT) QI meetings were held within the adult service to identify whatwas considered a successful transfer of care. We observed the first in-person transition clinic since the pandemic, and distributed electronic surveys of the clinic experience to pwCF, carers, and staff. Lastly, we held a virtual cross-service QI meeting to present findings, aiming to reach consensus on areas for change. Results: 5/5 pwCF and 5/5 carers completed the clinic surveys. Both identified their main priorities: to meet the adult team and receive a clinical review. Comments identified anxiety discussing future life plans too young or repetitively. 3/5 pwCF and 3/5 carers preferred the carer to be present throughout the visit. 7/9 staff completed the survey. There was general agreement of clinic objectives that 6/7 felt were met. Comments were around clinic location, pre-meeting, and coordinating MDTreviewcontent. Holding a face-to-face clinic was perceived as important. Overall, the MDTs agreed on 5 areas for improvement: documentation;patient information;clinic meetings;individual profession handovers;and identifying pwCF requiring bespoke transition. Conclusion: Protected time for QI provided a forum to bring paediatric and adult CF teams together to identify shared priorities for improvement of local transition care. A QI lead role has allowed us to drive service development during the COVID-19 pandemic and introduction of CFTR modulators.
ABSTRACT
Background: CFTR modulators have led to improvements in CF outcomes, including FEV1, exacerbation frequency and body mass index (BMI). Despite positive outcomes, modulators have brought new challenges – particularly elevated BMI. For many, weight gain has been due to increased fat rather than muscle mass, making exercise a high priority. Exercise has always been an integral part of CF management. However, the COVID-19 pandemic has made it harder for patients to access exercise. This presented a service need to set up a platform where patients could safely exercise at home with support from a known physiotherapist. Objectives: To assess the feasibility and acceptability of a physiotherapyled online group exercise class for CF patients. Methods: In this pilot study, high and low intensity virtual exercise classes were delivered twice weekly over four weeks. Eight participants were recruited;five completed the study. The primary outcomes were (1) feasibility, assessed by means, resources and time needed to deliver the intervention and (2) acceptability, assessed by qualitative interviews with participants. FEV1, BMI, 60STS and psychosocial outcomes were also monitored. Results: Time, resources and equipment were all adequate to deliver the intervention within the service. Positive themes from interviews included: (1) Impact on health: improved fitness, (2) Motivation to exercise: feeling encouraged, supported and accountable, and (3) Convenience: saved time, money and ease of exercising at home. Some challenges patients reported were space, technical issues with equipment and missing face-to-face interaction. Conclusion: Virtual exercise classes for patients with CF are both feasible and acceptable, with patients reporting a positive impact on their fitness levels as well as reduced travel burden. Patients also stated that classes delivered by a familiar physiotherapist motivated them to exercise and instilled confidence that the exercises were safe and effective.Background: CFTR modulators have led to improvements in CF outcomes, including FEV1, exacerbation frequency and body mass index (BMI). Despite positive outcomes, modulators have brought new challenges – particularly elevated BMI. For many, weight gain has been due to increased fat rather than muscle mass, making exercise a high priority. Exercise has always been an integral part of CF management. However, the COVID-19 pandemic has made it harder for patients to access exercise. This presented a service need to set up a platform where patients could safely exercise at home with support from a known physiotherapist. Objectives: To assess the feasibility and acceptability of a physiotherapyled online group exercise class for CF patients. Methods: In this pilot study, high and low intensity virtual exercise classes were delivered twice weekly over four weeks. Eight participants were recruited;five completed the study. The primary outcomes were (1) feasibility, assessed by means, resources and time needed to deliver the intervention and (2) acceptability, assessed by qualitative interviews with participants. FEV1, BMI, 60STS and psychosocial outcomes were also monitored. Results: Time, resources and equipment were all adequate to deliver the intervention within the service. Positive themes from interviews included: (1) Impact on health: improved fitness, (2) Motivation to exercise: feeling encouraged, supported and accountable, and (3) Convenience: saved time, money and ease of exercising at home. Some challenges patients reported were space, technical issues with equipment and missing face-to-face interaction. Conclusion: Virtual exercise classes for patients with CF are both feasible and acceptable, with patients reporting a positive impact on their fitness levels as well as reduced travel burden. Patients also stated that classes delivered by a familiar physiotherapist motivated them to exercise and instilled confidence that the exercises were safe and effective.
ABSTRACT
The COVID-19 pandemic has had a significant impact on the mental health and well-being of children and young people. A large scale survey undertaken by the NHS in July 2020 showed 1 in 6 children aged 5–16 had a probable mental health disorder compared to 1 in 9 in 2017. The TIDES study showed that young people with cystic fibrosis have a 2–3 times higher risk for anxiety and depression than the general population. There are also increasing reports of adverse mental health effects with CFTR modulators. We present the case of an adolescent girl with cystic fibrosiswho struggled with mental health issues since the start of the COVID-19 pandemic. This escalated during repeated lockdowns and on starting Kaftrio® in late 2020. Despite a beneficial effect initially on her lung function, her mental health deteriorated further and she was acutely admitted to a medical ward in spring 2021 with significant depression and passive suicidal ideation. She had lost 10% of her body weight in 3 months and had a nearly 20% drop in FEV1 in 5 months. Her escalating mental health condition lead to her being sectioned under the mental health act. We discuss the complexities of this case, managing a joint psychiatric and medical patient on an acute medical ward and the legalities of trying to ensure she had good cystic fibrosis care while under a mental health act section. Legally, the mental health act only covers treatment for mental health conditions but she was using non-compliance with CF care as a method of self-harming. We discuss the potential negative impact of Kaftrio® on her mental health and how we stopped and then slowly increased her dose using sweat tests and monitoring her mental health. Despite the challenges involved, her mental and physical health improved through coordinated working with all the teams involved in her care.
ABSTRACT
98% of male CF patients have congenital bilateral absence of the vas deferens leading to hypofertility. CF patients’ life expectancy and quality of life have improved, especially with CFTR modulators, and access to paternity is an increasingly unavoidable subject. In 2020, we built a therapeutic education program to improve patients’ knowledge and facilitate their decision-making regarding spermatozoid’s conservation ( A-1117-0011-00309 43rd ECFC). Development of e-health and the context of the COVID-19 pandemic led us to build an e-learning program. Methods and objectives: Our working group, including CF patients and parents, teamed up with an e-learning solutions expert agency. We wanted to facilitate access to training and better respect patients’ receptiveness to receive this sensitive information. The patient could review on his own after a face-to-face session. The objective was to broaden access for the parents and partners of boys and men with CF and provide a solid basis for discussion between patients and caregivers. Results: This e-learning training is available on PC and Smartphone. Patient data are protected according to French regulations. The training consists of 5 independent modules 1: Initial knowledge self-assessment, 2: CF male hypofertility, 3: Spermogram with a motion design on its practical modalities, 4: Surgical collection of sperm, 5: Video testimony of a patient, and a satisfaction questionnaire. Discussion: We started the program in June 2020 with voluntary patients. We submitted this work to the GETHEM (French National Therapeutic Education Working Group) in June 2021, which validated its promotion at the national level in October 2021. This program has been well received but the number of connections remains low (17 professional, 10 patients). The subject requires an adoption time by caregivers, and will re-launch in 2022. An additional module concerning genetic transmission of the disease to children as a CF parent is underway.
ABSTRACT
From September 2020 until January 2022, children with CF in the UK aged 6–12 years homozygous for F508del had a choice of CFTR modulators: Lumacaftor/ivacaftor(LUM/IVA) or tezacaftor/ivacaftor (TEZ/IVA)+ ivacaftor (IVA). Although benefit of the individual agents has been demonstrated in clinical trials, there is no direct comparison between treatments.1 Objectives: Review of Forced Expiratory Volume in 1 second (FEV1) and nutritional clinical benefits of switching from LUM/IVA to TEZ/IVA + IVA. Method: A retrospective review of 18 paediatric patients (pts) swapped from LUM/IVA to TEZ/IVA + IVA. Data collected of length of time on each CFTR modulator, body mass index (BMI) centile, FEV1 (% predicted and zscore). FEV1 data analysed using ANOVA test. Results: 12 female;6 male pts (Mean age 9 yrs 6mths (range 8–12 years)). Two pts swapped from LUM/IVA due to tolerability issues. The other families chose to swap. Mean length of time was 13 mths (±1.3) on LUM/IVA and 9mths ± 1.2 on TEZ/IVA + IVA. Spirometry;table 1 (Table Presented) Conclusion: Swapping CFTR modulators for most pts offered no clear improvement in FEV1 or BMI, the surrogate markers of lung and nutritional health. However, pts did not experience the usual decline in FEV1 seen in CF. There are many potential confounding factors that need to be considered, including that data was collected during the COVID pandemic. As new modulators are developed, further research will be required to better understand their mechanism of action in individual pts to guide optimal personalised prescribing. 1 Walker S., et al., A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11years with cystic fibrosis, J CYST FIBROS;June 2019;18(708–713).
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The proceedings contain 286 papers. The topics discussed include: is there still a place for methotrexate in severe psoriatic arthritis?;Improving availability of naloxone: an emergency;national pharmacovigilance surveillance of Astrazeneca Covid-19 vaccine (ChAdOx1-S vaccine);recommendations of the French Society of Rheumatology and the French Society of Physical Medicine and Rehabilitation on the non-pharmacological management of knee osteoarthritis;management of drug?drug interactions with nirmatrelvir/ritonavir in patients treated for Covid-19: guidelines from the French Society of Pharmacology and Therapeutics (SFPT);adverse events associated with JAK inhibitors;impact of the new CFTR modulators treatment on the respiratory epithelium;pharmacokinetics study showed increased brain delivery of anti-PD-1 after ultrasound-mediated blood-brain barrier in glioblastoma mouse models;and modulation of HCN channel activity in oxaliplatin-induced peripheral neuropathy.